Tauopathies are a diverse group of neurodegenerative diseases characterized by the accumulation of aggregated tau protein. Recent evidence suggests that transcellular spread of misfolded tau leads to the stereotypical progression of pathology observed in these diseases. Different tau aggregate conformations, or strains, may lead to the phenotypic diversity and unique patterns of spread of pathology observed in tauopathies, as has been observed in transmissible spongiform encephalopathies (TSEs). We have recently isolated distinct tau strains that stably propagate unique aggregate conformations in cell culture. Injection of these unique cellular tau strains into a murine tauopathy model produces different patterns of tau histopathology, suggesting conformation may indeed influence the pattern of tau pathology. This proposal will use this strain inoculation model to test whether different tau conformations can stably propagate in vivo. This will directly test whether tau can act as a true prion in an animal system. This proposal will then test the effect of conformation on the pattern of spread of tau pathology through the brain. This will test whether distinct tau aggregate conformations can lead to unique patterns of pathology, and will provide critical insight into the pathophysiology that underlies tauopathies. Finally, this proposa will test whether inhibition of heparan sulfate proteoglycan (HSPG) synthesis, which is required for endocytosis of aggregated tau, can prevent this spread of tau pathology. This will test HSPG-mediated uptake as a novel therapeutic target, and will provide mechanistic insight into the progression of tau pathology.